If a terrorist attack or industrial accident exposed large numbers of people to chemical toxins, there are few medicinal countermeasures that could be deployed in response. Therefore, the National Institutes of Health created Countermeasures Against Chemical Threats (CounterACT) to take a leadership role in pursuing the development of new and improved medical countermeasures designed to prevent and treat the conditions caused by potential and existing chemical agents of terrorism or released from transportation and storage facilities by industrial accidents or during a natural disaster.
Among the most prevalent threats are mustard compounds, which are considered “Higher Priority Chemical Threats” by NIH CounterACT, as these are easily and cheaply synthesized by conventional chemistry techniques and can be widely dispersed as a gas. This class of agents share a canonical structure, BCH2CH2X, where X is any leaving group (typically chloride) and B is a Lewis base, usually either sulfur (sulfur mustard) or nitrogen (nitrogen mustard). The mechanism of toxicity of mustards is complex. The most well-known effects are due to the cross-linking of adjacent DNA strands by reactive substitution of the chlorides into the nucleic acid base structure. However, additional mechanisms are also proposed, including Ca2+ leakage and oxidative insult from lipid peroxidation. These effects are also found with ionizing radiation. Indeed, the effects of mustard agents on cells is so similar to ionizing radiation that mustard agents are sometimes called radiomimetic compounds. Mustard gas can penetrate clothing and other permeable shields and damage begins within minutes of exposure. Initial organs affected include exposed areas such as skin, eyes, and lungs. Mustard compounds are well known as vesicants, causing extensive blistering of the skin. However, the skin not only accumulates but also distributes mustard to other tissues by releasing up to 90% of its absorbed dose into the circulation so that systemic exposure and multi-organ toxicity results. Pulmonary toxicity is chief among these, as the lungs receive both systemic and direct exposure from inhalation, and forms the principle cause of death in patients exposed to mustard gas. In the First World War, respiratory injury from vapor exposures resulted in death due to pneumonia secondary to chemical pneumonitis. Even more profound effects were seen in the Iran-Iraq war of the late 1980's, where a first wave of deaths occurred within three days of exposure from extreme injury to respiratory epithelium and alveoli, followed by a second wave of deaths between one and three weeks post-exposure from secondary bronchopneumonia and sepsis due to marrow failure. Although mustard gas and other chemical weapons are feared for their use as weapons of terror, another major threat of mustard gas exists. Tons of this chemical agent were produced for war, then subsequently buried in landfills, disposed of at sea, or left to decay in storage facilities.